Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK)

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. PATIENTS AND METHODS: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. RESULTS: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. CONCLUSIONS: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival.     

Success and failures in urban transport planning in Europe—understanding the transport system

Technological determinism has become a kind of religion for many people since it appears to offer solutions for societal problems as never before in history. Transport is one of the fascinating technology branches developed during the last 200 years. Effortless movement over long distances has become possible for car users as long as cheap fossil energy is available. However, the effect of fast transport on urban structures and society was not taken into account when developing these technical means. Technologists and economists have used indicators for expected benefits of these fast transport modes without taking into account the real system effects on society and urban structures. Plausible assumptions and hopes instead of scientific understanding of the complex system are used in practice. In contradiction to widely held beliefs of transportation planners, there is actually no growth of mobility if counted in number of trips per person per day, no time saving by increasing speed in the system, and no real freedom of modal choice. Modal choice is dependent on physical and other structures, the artificial environment built by urban planners, transport experts and political decisions. The core hypothesis of traditional urban and transport planning ‘growth of mobility’, ‘travel time saving by increasing speed’ and ‘freedom of modal choice’ are myths and do not exist in the real urban and transport system. This is the reason why urban planning and transport planning based on traditional non-scientific assumptions is creating continuously not only more transport problems, but also environmental and social as well as economic problems all over the world, where these principals are applied. Urban transport planning in Europe, understanding the transport system and the solutions are presented in this paper.     

Validation of the performance of a GMO multiplex screening assay based on microarray detection

A new screening method for the detection and identification of GMO, based on the use of multiplex PCR followed by microarray, has been developed and is presented. The technology is based on the identification of quite ubiquitous GMO genetic target elements first amplified by PCR, followed by direct hybridisation of the amplicons on a predefined microarray (DualChip^® GMO, Eppendorf, Germany). The validation was performed within the framework of a European project (Co-Extra, contract no 007158) and in collaboration with 12 laboratories specialised in GMO detection. The present study reports the strategy and the results of an ISO complying validation of the method carried out through an inter-laboratory study. Sets of blind samples were provided consisting of DNA reference materials covering all the elements detectable by specific probes present on the array. The GMO concentrations varied from 1% down to 0.045%. In addition, a mixture of two GMO events (0.1% RRS diluted in 100% TOPAS19/2) was incorporated in the study to test the robustness of the assay in extreme conditions. Data were processed according to ISO 5725 standard. The method was evaluated with predefined performance criteria with respect to the EC CRL method acceptance criteria. The overall method performance met the acceptance criteria; in particular, the results showed that the method is suitable for the detection of the different target elements at 0.1% concentration of GMO with a 95% accuracy rate. This collaborative trial showed that the method can be considered as fit for the purpose of screening with respect to its intra- and inter-laboratory accuracy. The results demonstrated the validity of combining multiplex PCR with array detection as provided by the DualChip^® GMO (Eppendorf, Germany) for the screening of GMO. The results showed that the technology is robust, practical and suitable as a screening tool.     

Impairment of long-term associative memory in aging snails (Lymnaea stagnalis).

Age-dependent impairment in learning and memory functions occurs in many animal species, including humans. Although cell death contributes to age-related cognitive impairment in pathological forms of aging, learning and memory deficiencies develop with age even without substantial cell death. The molecular and cellular basis of this biological aging process is not well understood but seems to involve a decline in the aging brain's capacity for experience-dependent plasticity. To aid in resolving this issue, we used a simple snail appetitive classical conditioning paradigm in which the underlying molecular, cellular, and neural network functions can be directly linked to age-associated learning and memory performance (i.e., the Lymnaea stagnalis feeding system). Our results indicate that age does not affect the acquisition of appetitive memory but that retention and/or consolidation of long-term memory become progressively impaired with advancing age. The latter phenomenon correlates with declining electrophysiological excitability in key neurons controlling the feeding behavior. Together, these results present the Lymnaea feeding system as a powerful paradigm for investigations of cellular and molecular foundations of biological aging in the brain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of molecular tilt angle on the SHG response of pyroelectric liquid crystal polymers

Second harmonic generation in novel pyroelectric liquid crystal polymers (PLCP) made from a series binary mixtures, was studied using 1100 nm as the fundamental wavelength. The PLCPs were prepared by photo-polymerization of binary mixtures of two monomers which exhibit a smectic C^* phase, A2c (4″-(R)-(−)-2-[(10-acrylo-yloxy)decyl]oxy-3-nitrophenyl 4-{4′-[(11-acryloyloxy)-undecyloxy]phenyl}benzoate) and Alb (4″-((R)-(+)-2-octyloxy)-3″-nitrophenyl 4-(4′-(11-acryloyloxy)undecyloxy)-phenyl)-benzoate). The highest d₁₆ and d₂₃ coefficients were found to be in the range 0.65–0.8 pm/V, and differed depending on the detailed preparation of the sample. All cases of polymers formed from the chiral smectic C* phase showed an SHG-signal with no external field present, indicating that polar order became fixed. The SHG-signal was found to increase with the tilt angle of the FLC molecules.     

Occupational Factors and 5-Year Weight Change Among Men in a Danish National Cohort.

This study explored whether factors related to the work environment could predict changes in body mass index (BMI) and whether the effect of psychosocial factors was dependent on baseline BMI. The sample consisted of 1,980 male employees from the Danish National Work Environment Cohort Study. Changes in BMI between 1995 and 2000 were analyzed, by multiple regression, as a function of background variables and a series of occupational variables obtained in 1995. Age, baseline BMI, job insecurity, and psychological demands predicted changes in BMI. Job insecurity and high or low psychological demands increased the likelihood of weight gain among obese employees, whereas they increased the likelihood of weight loss among employees with a low BMI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Qualitative differences in response bias from spatial cueing.

Examined 2 response bias parameters in a spatial cueing paradigm: (1) "cued location (CL) bias," the relative probability with which a signal is incorrectly assigned to the CL; and (2) "likelihood ratio (beta)," the amount of evidence required to decide that a signal appeared at a particular CL or un-CL. The 2 parameters were found to be differentially sensitive to stimulus onset asynchrony (SOA) between peripheral cue and target. CL bias was strongly affected by SOA, decreasing within 300 msec after peripheral cue onset. In contrast, the difference in beta between CLs and un-CLs was independent of SOA. This suggests that CL bias reflects strong but transitory pathway preactivation following a peripheral cue. In contrast, beta effects predominantly reflect "late" decision-making processes that differentially weight the sensory evidence from CLs and un-CLs according to their a priori signal probabilities. (French abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Auffinden von verschleierter Malware

Malware-Autoren setzen zunehmend Verschleierungsmechanismen wie Komprimierung, Verschlüsselung oder sich selbst modifizierenden Programmcode ein, welche das Auffinden der Malware durch herk?mmliche Virenerkennungsverfahren wie zum Beispiel die signaturbasierte Suche sehr mühsam und teilweise sogar erfolglos erscheinen lassen. Ein erfolgversprechender Ansatz, um auch unbekannte Viren, Würmer oder Trojaner zu erkennen, ist die heuristische Analyse